Assistance Mary Lane, PhD -- Data analysis Shannie Frisbie -- Cost information The residents and fellows for providing me with the opportunity to use rFVIIa
FDA Approved Uses for rFactor VIIa “…management of bleeding related to hemophilia in patients with factor inhibitors…” A number of “off label” uses have become popular since it was first used for treatment of traumatic bleeding after a GSW in 1999
Clotting Factor Changes in CPB Decrease in Factors may be important in CPB Harker -- decrease in Factors not important Based on observations of single deficiency pts The following changes have been observed : Factor II51% Decrease Factor V28% Decrease Falls before CPB Less fall with adequate heparinization Factor VII27% Decrease Ca. 28% fall in the PCV due to dilution Factor X56% Decrease Factor VIIINo Change Davidson, et al. Blood Coagulation & Fibrinolysis 2003; 14:175-79.
rFactor VIIa Mechanism of Action 406 amino acid Vitamin K-dependent glycoprotein Generation of thrombin by initial binding to tissue factor and activation of FX on the platelet surface It also participates in conversion FIX-->FIXa Activation of FX in combination with FV converts prothrombin to thrombin leading to the formation of a hemostatic “plug” & subsequently converts fibrinogen to fibrin causing local hemostasis
rFactor VIIa Mechanism of Action Partial activation of thrombin occurs at rFVIIa concentrations of 50nM, but full activation of thrombin or “thrombin burst” occurs at 100-150nM This thrombin activity on the platelet leads to a stabilized thrombin plug and tight fibrin structure resistant to lysis
rFactor VIIa Mechanism of Action The “thrombin burst” and stabilized “plug” seems to only occur at sites where tissue factor is exposed at sites of vessel injury This is probably why there is little generalized thrombosis with rFVIIa
rFactor VIIa Mechanism of Action The decrease in fibrinolysis is thought to possibly be due to an increase in thrombin- activatable fibrinolysis inhibitor and an increase in FXIIIa rFVIIa appears to work in a TF-independent fashion directly on FIX/FX on the phospholipid surface of the activated platelet
Hemostatic Mechanisms for rFVIIa Eikelboom, et al. Blood Coagulation & Fibrinolysis 2003, 14:713-17.
rFactor VIIa Half Life The mean elimination half life of rFVIIa is 3.8-5.8 hours (only 1.3 hours in children) Prothrombin time is shortened by rFVIIa treatment
rFactor VIIa Dosing Dosage Micrograms/Kg Time to Treatment Excellent or Effective Response % Mean Number of Doses Compassionate Use 60-1205 days7213.6 Dose Finding709 hours723.6 359 hours533.5 US Home Treatment 901.2 hours922.3
rFactor VIIa Dosing Most authors will admit that there is little real science for the dosing of rFVIIa and most authorities recommend that the dosing be based on weight, but that the dose be rounded to the nearest vial Continuous infusions do not seem to provide any benefit and the dosing scheme is no more clear than bolus
Adverse Effects of rFVIIa As of March 2001, an estimated 171,790 doses had been sold with 87 reported adverse events: 16 Decreased therapuetic response 7 MI’s (all pt’s had predisposing factors) 4 PE’s 6 Ischemic CVA’s 3 Venous Thromboses 1 DIC 17 died and 8 were felt to be related to the rFVIIa 1:21,474 related to rFVIIa Novo Nordisk data, rFVIIa, 20 March 2001.
Adverse Effects of rFVIIa Levi et al reviewed 483 papers related to the pharmacologic use of rFVIIa Used for hemophilia with inhibiting antibodies, Glanzmann Thrombasthenia, congenital FVII deficiency, liver disease, cirrhosis, surgery/trauma, reversal of anticoagulant therapy, and excessive blood loss They found that in patients other than hemophilia patients the estimated incidence of thromboembolism is 1.4% Levi, et al. Crit Care Med 2005; 33:883-90.
Surgical Uses of rFVIIa Raobaikady et al looked at the use of rFVIIa in a double-blind, randomized, placebo- controlled study in 48 patients undergoing surgery for major traumatic fracture of the pelvis or the pelvis/acetabulum and found no decrease in the volume of blood loss in patients with normal hemostasis Raobaikady, et al. BJA 94(5):586-91.
Cardiac Surgery and rFVIIa Karkouti et al looked at 51 patients with intractable blood loss after cardiac surgery using a propensity score- matched case-control analysis They used about 70micrograms/kg in severe bleeding and 35micrograms/kg in “less severe, controlled bleeding” Karkouti, et al. Transfusion 2005; 45:26-34.
Characteristics of Karkouti Pts VARIABLErFVIIa PATIENTS %GENERAL POP %p VALUE Mean Age56620.0007 Urgent Surgery278<0.0001 Redo Surgery358<0.0001 CHF4821<0.0001 Active Endocarditis81<0.0001 Complex Surgery7324<0.0001 Mean CPB Period (min)159100<0.0001 DHCA153<0.0001 Difficult Wean from CPB4613<0.0001 LCOS254<0.0001 Reexploration606<0.0001 Massive Blood Loss928<0.0001 Units Blood, Cryoppt100<0.0001 PRBC141<0.0001 Platelets150<0.0001 FFP100<0.0001 Karkouti, et al. Transfusion 2005; 45:26-34.
Matched Control Pts The matched control patients were essentially no different from the rFVIIa patients except in the volume of blood products that they received Karkouti, et al. Transfusion 2005; 45:26-34.
Karkouti Conclusions The hourly blood loss profile after the administration of rFVIIa is similar to that seen in the control and is significant 1/3 of the patients required a second dose and all of those patients had a surgically correctable cause rFVIIa was found to reduce intractable blood loss, but with an increase in morbidity ICU LOS, Hosp LOS, Renal Dysfunction, ? CVA Karkouti, et al. Transfusion 2005; 45:26-34.
Cardiac Surgery and rFVIIa Raivio et al reported the use of rFVIIa in 16 postop cardiac surgery patients 10 patients were “emergency” 6 patients required DHCA 4 were redo patients All were complex cardiac or aortic procedures Mean predicted EuroSCORE mortality was 19.8% Hospital mortality was 25% Mean ICU stay was 21 days Mean dose was 65 micrograms/kg Ravio et al, Ann Thorac Surg 2005; 80:66-71.
Raivio Bleeding Pre/Post rFVIIa 6 Hours Before rFVIIa 6 Hours After rFVIIa p Value Bleeding (ml)2180350<0.001 Transfusions (Units) Platelets1200.005 FFP3.01.00.017 PRBC4.02.0NS Ravio et al, Ann Thorac Surg 2005; 80:66-71.
Raivio Conclusions 82% of the patients had an obvious hemostatic response 25% had “severe postoperative thromboembolic or thrombotic complications” All of the Heart or Heart/Lung transplant patients died They recommend caution in the use of rFVIIa Ravio et al, Ann Thorac Surg 2005; 80:66-71.
Cost Concerns The cost of rFVIIa is significant 1.2 mg, 2.4mg, and 4.8 mg vials 2.4 mg “costs” $850 at VAMC 2.4 mg “costs” $2184 at OUMC Estimated cost in literature is about $5000 for a 90 mcg/kg dose in a 70kg patient Cost to OUMC 8/04-8/05 for 46 doses in 35 patients was $299,240 However, the cost of intractable bleeding is also high Average incremental increase in cost of $3,866 Bleeding requiring reexploration increases mortality 7-fold (15.4%) and the additional cost is $10,000
Oklahoma City VAMC and rFVIIa rFVIIa was first used at the OKC VAMC for intractable post-Cardiotomy bleeding in December 2002 Since that time 16/564 patients have received rFVIIa
Demographics 16 patients Mean Age 63.9 yrs (54-76) Elective37.5% Urgent43.75% Emergency18.75% Amicar18.75% Aprotinin75% Nothing6.25% Few of these patients were receiving IIb/IIIa inhibitors/Plavix
Patient Characteristics Mean Preop EF49% Mean rFVII Dose87.83 mcg/kg Mean NYHA/CCS3.19/2.94 Mean CPB Time211 min One OPCAB Patient Mean Operative Time413 min Mean Intubation Time53 hours Mean SICU Days7.0 days Mean Hospitalization Days11.45 days
Outcomes 2/16 patients were returned to the OR for re- exploration One was bleeding from a side branch of a SVG One had stopped bleeding and had only about 250-500ml of blood total in the left chest and mediastinum This represents all of the patients returned (with or without rFVIIa) for the past 4 years
Mortality 6/16 patients died 1/16 (6.25%) died in the OR/within 30 days 5/16 died from 36 to 208 days later 31.25% overall mortality for these patients Overall mortality 4.1% (23/564) from 12/02-7/05 5/16 of these deaths were attributed as Operative Mortality by CICSP and these are included in the 4.1%
Future Directions rFVIIa, while expensive, may be less expensive than re-exploration rFVIIa may salvage some patients who otherwise would not have survived Is there a role for rFVIIa earlier in the care of these patients?
Other Issues Other Off-label uses for rFVIIa Relative contraindications to transfusion Multiple RBC allo-antibodies Refractoriness to platelet transfusions ?? Plavix poisoning IgA deficiency who should not get FFP Jehovah’s Witnesses When is the best time to give rFVIIa? Who decides who gets and when to give rFVIIa?